What are the potential effects of Metformin (metformin hydrochloride) on the fetus and mother during pregnancy?

From the Guidelines

Metformin use during pregnancy is associated with potential effects on the fetus and mother, including a higher risk of preterm birth, smaller neonatal birth weights, and increased risk of small-for-gestational-age neonates.

Potential Effects on the Fetus

• Metformin crosses the placenta, resulting in umbilical cord blood levels of metformin as high or higher than simultaneous maternal levels 1
• Exposure to metformin in utero has been associated with higher BMI, waist-to-height ratio, and waist circumference in offspring at 7-9 years of age 1
• A meta-analysis demonstrated that metformin exposure resulted in smaller neonates with an acceleration of postnatal growth, resulting in higher BMI in childhood 1

Potential Effects on the Mother

• Metformin use during pregnancy has been associated with less maternal weight gain compared to insulin therapy 1
• Metformin may be associated with a lower risk of neonatal hypoglycemia compared to insulin therapy 1
• However, metformin treatment monotherapy failure occurred in 14-46% of individuals, and women using metformin were twice as likely to need insulin as women using glyburide 1

Recommendations

• Insulin is the preferred medication for treating hyperglycemia in gestational diabetes mellitus, and metformin should not be used as a first-line agent 1
• Metformin may be considered as an alternative to insulin for women who are unable or unwilling to use insulin, but its use should be carefully monitored and adjusted as needed 1

From the FDA Drug Label

Limited data with metformin hydrochloride tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

The potential effects of Metformin on the fetus and mother during pregnancy include:

• Risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy, such as:
  • Diabetic ketoacidosis
  • Pre-eclampsia
  • Spontaneous abortions
  • Preterm delivery
  • Stillbirth
  • Delivery complications
• Fetal risks associated with poorly controlled diabetes mellitus, such as:
  • Major birth defects
  • Stillbirth
  • Macrosomia related morbidity However, the limited data available do not suggest a clear association between metformin use and major birth defects or miscarriage risk 2.

From the Research

Potential Effects of Metformin on the Fetus

• Metformin can cross the placenta and enter the fetal circulation, potentially affecting fetal growth and development 3, 4, 5
• Studies have shown that metformin exposure during pregnancy may lead to fetal growth restriction and increased risk of being born small for gestational age (SGA) 3, 4
• Metformin may also affect placental structure and function, leading to reduced placental efficiency and altered fetal development 3

Potential Effects of Metformin on the Mother

• Metformin has been shown to improve maternal glucose tolerance and reduce maternal fat mass in obese pregnant women 3
• Metformin may also improve uterine artery compliance and reduce the risk of maternal complications associated with gestational diabetes mellitus (GDM) 3, 6
• However, metformin may not prevent fetal growth restriction or placental aging, despite improving maternal metabolic health 3

Long-Term Effects of Metformin Exposure

• There is evidence to suggest that metformin exposure during pregnancy may have long-term effects on the offspring's metabolic health, including increased risk of obesity and cardiometabolic diseases 4, 7
• The mechanisms by which metformin affects fetal growth and long-term health are not fully understood and require further research 4, 6
• More studies are needed to assess the impact of metformin on offspring development and metabolic function, particularly in the context of GDM and type 2 diabetes 7, 6